WO1994002464A1 - Nouveaux derives de pyridine a effet antagoniste contre les leucotrienes b¿4? - Google Patents

Nouveaux derives de pyridine a effet antagoniste contre les leucotrienes b¿4? Download PDF

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Publication number
WO1994002464A1
WO1994002464A1 PCT/DE1993/000593 DE9300593W WO9402464A1 WO 1994002464 A1 WO1994002464 A1 WO 1994002464A1 DE 9300593 W DE9300593 W DE 9300593W WO 9402464 A1 WO9402464 A1 WO 9402464A1
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Prior art keywords
pyridyl
propionic acid
group
methoxyphenyl
hexenyloxy
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PCT/DE1993/000593
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German (de)
English (en)
Inventor
Josef Heindl
Werner Skuballa
Bernd Buchmann
Wolfgang Fröhlich
Roland Ekerdt
Claudia Giesen
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Schering Aktiengesellschaft
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Priority to JP6503890A priority Critical patent/JPH07508990A/ja
Priority to AU44153/93A priority patent/AU679184B2/en
Priority to EP93914599A priority patent/EP0651745A1/fr
Priority to US08/374,608 priority patent/US5624943A/en
Publication of WO1994002464A1 publication Critical patent/WO1994002464A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

Definitions

  • the invention relates to new pyridine derivatives Effect, a process for their preparation and their use as a medicament.
  • LTB4 is an important inflammation mediator for inflammatory diseases in which leukocytes migrate into the diseased tissue. The effects of LTB4 are triggered at the cellular level by the binding of LTB4 to a specific receptor.
  • LTB4 is known to cause leukocyte adhesion to the blood vessel wall.
  • LTB4 is chemotactically active, ie it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration. It also indirectly changes vascular permeability due to its chemotactic activity, a synergism with prostaglandin E2 being observed.
  • LTB4 obviously plays a crucial role in inflammatory, allergic and immunological processes.
  • Leukotrienes and especially LTB4 are involved in skin diseases that are associated with inflammatory processes (increased vascular permeability and edema, cell infiltration), increased proliferation of skin cells and itching, such as eczema, erythema, psoriasis, pruritus and a ne.
  • Pathologically elevated leukotriene concentrations are either causally involved in the development of many dermatitis, or there is a connection between the persistence of the dermatitis and the leukotrienes.
  • Significantly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis or atopic denatitis.
  • Leukotrienes and especially LTB4 are also involved in diseases of internal organs for which an acute or chronic inflammatory component has been described; e.g.
  • Joint diseases arthritis
  • Diseases of the respiratory tract asthma, rhimtis and allergies
  • inflammatory bowel diseases colitis
  • reperfusion damage to cardiac, intestinal, or kidney tissue caused by the second pathological occlusion of blood vessels.
  • leukotrienes and especially LTB4 are involved in the disease in multiple sclerosis and in the clinical appearance of the shock (triggered by infections, burns or complications in kidney dialysis or other extracorporeal perfusion techniques).
  • Leukotrienes and especially LTB4 also have an influence on the formation of white blood cells in the bone marrow, on the growth of smooth muscle cells, of keratinocytes and of B-lymphocytes. LTB4 is therefore involved in diseases with inflammatory processes and in diseases with pathologically increased formation and growth of cells.
  • V denotes a single bond, a phenyl radical or a pyridyl radical
  • W represents a hydrogen atom, a halogen atom, an alkyl group with up to 4 carbon atoms, a trifluoromethyl group, an alkylsulfonylamino group, a trifluoromethylsulfonylamino group, an arylsulfonylaminocarbonyl group, a free, esterified or amidated carboxyl group, or a hydroxyl group,
  • Y represents an oxygen atom or a methylene group
  • Z is a single bond if q is the number 2 or otherwise an alkyl group or alkylene group with a maximum of 8 carbon atoms or one optionally substituted by alkyl groups with a maximum of 4 carbon atoms, alkoxy groups with a maximum of 4 carbon atoms, 1-oxoalkyl groups with a maximum of 4 carbon atoms, halogen atoms and / or trifluoromethyl groups Phenyl radical, phenoxy radical or styryl radical, and their salts with physiologically acceptable bases.
  • esterified or amidated carboxyl groups of the pyridine derivatives of the general formula I preference is given to those which are derived from physiologically acceptable alcohols or amines.
  • Physiologically acceptable alcohols with which the carboxyl groups can be esterified are, for example, straight-chain or branched or cyclic, saturated or unsaturated hydrocarbon radicals, which, if desired, have an oxygen atom or a Nitrogen atom can be interrupted, or with hydroxy groups.
  • Amino groups or carboxyl groups can be substituted, such as, for example, alkanoic (in particular those having 1 to 6 carbon atoms) alkenols, alkynols, cycloalkanols.
  • Cycloalkyl alkanols phenyl alkanols, phenyialkenoie, alkanediols. Hydroxycarboxylic acids, aminoalkenols or alkylaminoalkenols and dialkylaminoalkanoia with 1 to 4 carbon atoms in the alkyl radical.
  • Alcohols which are suitable for esterifying the carboxyl groups are, for example, those which contain methyl-carboxymethyl, ethyl-2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-carboxylethyl, propyl , Allyl, cyclopropylmethyl, isopropyl, 3-hydroxypropyl, propinyl, 3-aminopropyl, butyl, sec-butyl, tert-butyl, butyl (2) -, cyclobutyl, pentyl -, Isopentyl-, tert-pentyl-, 2-methylbutyl-, cyclopentyl-, hexyl-, cyclohexyl-, cyclo-2-enyl-, cyclopentylmethyl-, heptyl-, benzyl-, 2-phenylethyl-,
  • Suitable alcohols for the esterification are also those which are unstable, i.e. lead under physiological conditions esters, such as 5-hydroxyindane, acyloxymethanols, especially acetoxymethanol, pivaloyloxymethanol, 5-indanyloxycarbonylmethanol, glycolic acid, dialkylaminoalkanoia, especially dimethylaminopropanol, and hydroxyphthalide.
  • esters such as 5-hydroxyindane, acyloxymethanols, especially acetoxymethanol, pivaloyloxymethanol, 5-indanyloxycarbonylmethanol, glycolic acid, dialkylaminoalkanoia, especially dimethylaminopropanol, and hydroxyphthalide.
  • Preferred physiologically acceptable amines with which the carboxyl groups can be amidated are ammonia, alkylamines, dialkylamines, alkanolamines, dialkanolamines having 1 to 6 carbon atoms in the alkyl or alkanoi radical or five- or six-membered N-heterocycles.
  • suitable amines are: methylamine, ethylamine, isopropylamine, ethanamine, dimethylamine, diethylamine, diethanolamine, pyrrolidine, piperidine, morpholine or N-methylpiperazine.
  • alkylsulfonylamino group W is preferably to be understood as meaning a group which is derived from an alkyl group having a maximum of 4 carbon atoms.
  • the methylsulfonylamino group may be mentioned as an example.
  • An arylsulfonylaminocarbonyl group is understood to mean, for example, an alkylbenzenesulfonylaminocarbonyl group with up to 4 carbon atoms in the alkyl radical - such as, for example, the 4-methylbenzenesulfonylaminocarbonyl group.
  • physiologically acceptable salts of the carboxy group are the alkali metal or alkaline earth metal salts, such as the lithium or sodium salt. Potassium or the calcium salt, the ammonium salt, the trishydroxymethyl aminomethane salt and the copper (II) salt, salts with organic bases such as the piperazine salt or the methyl glucamine salt, and the salts of the pyridine derivatives with amino acids.
  • pyridine derivatives of the general formula I with Y in the meaning of an oxygen atom, n in the meaning of a number from 1 to 4, q in the meaning of the number 1 and Z in the meaning of an optionally by alkyl groups with a maximum of 4 Carbon atoms, alkoxy groups with a maximum of 4 carbon atoms and / or 1-oxoaikyl groups with a maximum of 4 carbon atoms of substituted phenyl radical,
  • Hydrogen atom or a halogen atom (in particular a bromine atom or iodine atom) and among these in turn those in which X, Y, z, r, q, ________; _ n and m have the meaning given under b), c) or d) and f) pyridine derivatives of the general formula I with p, U and V in the abovementioned meaning and W in the meaning of a hydrogen atom or a free, esterified or amidated carboxyl group and among these in particular those in which X, Y, r, q , : £ iii _ n and m have the meaning given under b), c) or d).
  • a halogen atom in particular a bromine atom or iodine atom
  • the invention further relates to a process for the preparation of the pyridine derivatives of the general formula I, which is characterized in that in a manner known per se
  • TA represents the same as Z but does not represent a single bond and Q represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, or condenses
  • Q ' represents a halogen atom or a trifluoromethanesulfonyloxy group, with a compound of the formula VI, VII or VIII
  • R ' represent lower alkyl radicals with a maximum of 4 carbon atoms
  • the process according to the invention according to variant a) is carried out under the conditions which are conventionally used for the alkylation of aromatic or heteroaromatic hydroxy compounds.
  • the compounds of the formula II can be alkylated with the compounds of the general formula III or IV in an inert solvent in the presence of alkali metal carbonates, such as potassium carbonate or cesium carbonate (J. Chem. Soc, Chem. Comm. 1979, 285), in the latter case, pyridine derivatives of the general formula I with q in the meaning of number 2 are obtained.
  • the synthesis according to process variant b) is also carried out in a manner known per se, for example by reacting the compounds of the formula V in the presence of organic palladium catalysts with the compounds of the formula VT, VII or VIII (Tetrahedron Letters 50, 1975, 4467 ff, Bull. Chem. Soc. Jpn. 60, 1987, 767 ff; Angewandte Chemie 99, 1987, 1285 ff, Tetrahedron Letters 26, 1985, 2667 ff).
  • the process according to variant o is carried out under the conditions which are customarily used in the so-called Wittig reactions (Chem. Ber. 94, 1961, 1373f).
  • the starting compounds required for the process according to the invention can also be synthesized in a manner known per se, for example by building the desired side chains under the conditions mentioned above, starting from the appropriately substituted halopyridines, pyridinaidehydes or hydroxypyridines esterified with trifluoromethanesulfonic acid.
  • the new pyridine derivatives are pha ⁇ na ologically effective compounds that are particularly characterized by a leukotriene-B4 antagonistic activity.
  • the pyridine derivatives of the general formula I are therefore anti-inflammatory, anti-allergic and anti-proliferative.
  • the compounds of the formula I are particularly suitable for topical application because they have a dissociation between the desired topical activity and undesirable systemic side effects.
  • the new pyridine derivatives of the formula I are suitable in combination with the auxiliaries and vehicles customary in pharmaceutical pharmacy for the local treatment of skin diseases in which leukotrienes play an important role, such as contact dermatitis, various types of eczema, neurodermatoses , Erythroderma, pruritis vulvae et ani, rosacea, erythematosus cutaneus, psoriasis, lying ruber planus et verrueosus and similar skin diseases.
  • skin diseases in which leukotrienes play an important role such as contact dermatitis, various types of eczema, neurodermatoses , Erythroderma, pruritis vulvae et ani, rosacea, erythematosus cutaneus, psoriasis, lying ruber planus et verrueosus and similar skin diseases.
  • the pharmaceutical specialties are produced in a conventional manner by converting the active ingredients into the desired application form, for example: solutions, lotions, ointments, creams or plasters, with suitable additives.
  • the active substance concentration depends on the form of administration.
  • an active ingredient concentration of 0.0001% to 3% is preferably used.
  • the new compounds if appropriate in combination with the usual carriers and auxiliary substances, are also well suited for the production of inhalants which can be used for the therapy of allergic diseases of the respiratory tract such as, for example, brochial asthma or rhinitis.
  • the new pyridine derivatives are also suitable in the form of capsules, tablets or dragées, which preferably contain 0.1 to 100 mg of active ingredient or are administered orally or in the form of suspensions, which preferably contain 1-200 mg of active ingredient per dose unit and rectally are also used to treat diseases of internal organs in which leukotrienes play an important role, such as allergic diseases of the intestinal tract, such as ulcerative colitis and granulomatous colitis.
  • the new leukotriene B4 antagonists are suitable for the treatment of multifunctional sclerosis and the symptoms of shock.
  • the new LTB4 antagonists are suitable not only for treating diseases of internal organs with inflammatory processes, but also for treating diseases with increased growth and the formation of cells in which leukotrienes play an important role. Examples are leukemia (increased growth of white blood cells) or arthereosclerosis (increased growth of smooth muscle cells from blood vessels).
  • leukemia increased growth of white blood cells
  • arthereosclerosis increased growth of smooth muscle cells from blood vessels.
  • the new pyridine derivatives can also be used in combination, e.g.
  • lipoxygenase inhibitors cyclooxygenase inhibitors, prostacyclin agonists, thromboxane antagonists, leukotriene D4 antagonists, leukotriene E4 antagonists, leukotriene F4 antagonists, phosphodiesterase inhibitors, calcium antagonists, PAF antagonists, or other known therapy forms of the illnesses or other known therapy forms used.
  • Example 1D The preparation of the (IE) -6-bromo-1- (4-methoxyphenyl) -l-hexene used in Example 1D is described in German patent application P 40 28 866.
  • Example 2A Under the conditions of Example 2A, 600 mg of methyl 3- ⁇ 3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -2-pyridyl ⁇ propionate are used in the presence of 940 mg of cesium carbonate Potassium carbonate reacted with 205 mg iodomethane, processed and the crude product on silica gel with hexane / 0-10% ethyl acetate chromatography. 570 mg of methyl 3- ⁇ 3- [3- (4-acetyl-3-methoxy-2-propylphenoxy) propoxy] -2-pyridyl ⁇ propionate are obtained as an oil.
  • Example 1 D Under the conditions of Example 1 D, 850 mg of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) propionate with 612 mg (IE) -6-bromo-l- (4-methoxyphenyl) -l- converted hexene, processed and the crude product chromatographed on silica gel with hexane / 0-5% ethyl acetate. 773 mg of 3- ⁇ 6-iodo-3- [6- (4-methoxyphenyl) -
  • Example 1E Under the conditions of Example 1E, a solution of 90 mg of 3- ⁇ 6-acetyl- 3- [6- (4-methoxyphenyl- (5E) -5-hexenyloxy] -2-pyridyl ⁇ propionic acid methyl ester in 1 ml Methanol was saponified and processed with 0.7 ml of 2N sodium hydroxide solution, and 73 mg of the title compound of melting point 89-90 ° C. are obtained.
  • the reaction mixture is filtered, the filter residue is washed with ethyl acetate and the filtrate is concentrated.
  • the residue is taken up in water, extracted with ethyl acetate, dried over sodium sulfate and concentrated.
  • the crude product is chromatographed on Kieseigel with hexane / 0-10% ethyl acetate and for complete purification of the high pressure liquid chromatography
  • Example 5 A Under the conditions of Example 5 A, 1 g of 3- ⁇ 6-iodo-3- [6- (4-methoxyphenyi) - (5E) -5-hexenyloxy] -2-pyridyl ⁇ propionic acid methyl ester with 320 mg of 3- Ethinylbenzoeklaremethylester implemented, processed and the crude product on Kieseigel with hexane / 0-15% ethyl acetate.
  • Example 5 A Under the conditions of Example 5 A, 1 g of 3- ⁇ 6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl ⁇ propionic acid methyl ester with 384 mg of 4- Ethinylbenzoeklaremethylester implemented, processed and the crude product on silica gel with hexane / 0-7% ethyl acetate.
  • Example 5 A Under the conditions of Example 5 A, 6.3 g of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) propionate are reacted with 3.28 g of methyl 4-ethynyl benzoate, processed and the crude product on silica gel with hexane / 0-50% Chromatographed ethyl acetate. 4.1 g of methyl 3- ⁇ 3-hydroxy-6- [2- (4-methoxycarbonylphenyi) -ethynyl] -2-pyridyl ⁇ propionate of melting point 173-177 ° C are obtained.
  • Example 1 D Under the conditions of Example 1 D, 500 mg of 3- ⁇ 3-hydroxy-6- [2- (4-methoxycarbonyiphenyl) ethynyl] -2-pyridyl ⁇ propionic acid methyl ester are reacted with 358 mg of 1-decyl bromide and processed. 531 mg of 3- ⁇ 6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3-decyloxy-2-pyridyl ⁇ -propionic acid methyl ester of melting point 88-90 ° C. are obtained.
  • 1.4 g of 3- ⁇ 6- [2- (4-methoxycarbonylphenyl) ethynyl] -3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy -propoxy] -2-pyridyl ⁇ -propionic acid methyl ester is reacted with 345 mg iodomethane and processed, 1.28 g of 3- ⁇ 6- [2- (4-methoxycarbonyiphenyl) -ethynyl] -3- [3- (4-acetyl -3-methoxy-2-propylphenoxy-propoxy] -2-pyridyl ⁇ -propionic acid methyl ester obtained as a yellow oil.
  • IR (KBr): 2960, 2880, 2215, 1705, 1680, 1608, 1590, 1458, 1415, 1360, 1275, 1222, 1120, 1060, 1020, 860, 830, 675 cm " 1 -
  • Example 1 D Under the conditions of Example 1 D, 500 mg of 3- ⁇ 3-hydroxy-6- [2- (4-methoxycarbonylphenyl) -ethynyl] -2-pyridyl ⁇ -propionic acid methyl ester with 354 mg of l-bromo- (3RS) - 3,7-dimethyl-6-octene reacted, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate.
  • 3RS l-bromo-
  • Example 3C Under the conditions of Example 3C 260 mg of 3- ⁇ 3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- (2-phenylethynyl) -2-pyridyl ⁇ -propionic acid- methyl ester in 2.5 ml of methanol and 2.5 ml of tetrahydrofuran with 5 ml of 1N sodium hydroxide solution and prepared. 201 mg of the title compound of melting point 121-123 ° C. are obtained.
  • IR (KBr): 3250 (wide), 2940, 2220, 1640, 1604, 1580, 1550, 1510, 1450, 1390, 1300, 1244, 1183, 1115, 1060, 960, 845, 808, 760, 680 cm "1
  • Example 1 D Under the conditions of Example 1 D, 10 g of 3-hydroxy-2-iodo-6-methylpyridine are reacted with 2.7 ml of iodomethane and processed. 10.5 g of 2-iodo-3-methoxy-6-methylpyridine with a melting point of 45-50 ° C. are obtained.
  • Example 1 D Under the conditions of Example 1 D, 9.8 g of 2-iodine-3-methoxy-pyridine-6-carboxylic acid are reacted with 2.5 ml of iodomethane and processed. 7.4 g of 2-iodo-3-methoxypyridine-6-carboxylic acid methyl ester of melting point 175-178 ° C. are obtained.
  • Lithiumchloric 3 1 ml of tetrahydrofuran added dropwise.
  • the reaction mixture is stirred for 5 minutes at ('), cooled again to -20 ° C., with a solution of 1.1 g of 2-iodo-3-me: oxypyridine-6-aldehyde in 2 ml of tetrahydrofuran and 2 ml of dichloromethane and 1, 9 ml of boron trifluoride-ethyl ether complex are added, the mixture is stirred for three hours at 0 ° C.
  • reaction mixture is poured into saturated ammonium chloride solution, the precipitate is suctioned off through diatomaceous earth, the filter residue is washed with ethyl acetate, the organic phase is separated off and the Water phase three more times shaken out with ethyl acetate.
  • the organic phase is dried over sodium sulfate, concentrated and the crude product is chromatographed on silica gel with hexane / 0-20% ethyl acetate. 1.11 g of (5RS) -5-hydroxy-5- (2-iodo-3-methoxy-6-pyridyl) pentanoic acid methyl ester are obtained as an oil.
  • IR film: 3440 (wide), 2948, 2840, 1720, 1580, 1463, 1435, 1364, 1263. 1202, 1165, 1112, 1018, 988, 833 cm '1
  • Example 1 D 70 mg of 5- [3-hydroxy-2-f2-methoxycarbonylethyl) -6-pyridyl] -5-oxopentanoic acid methyl ester with 58 mg (IE) -6-bromo-l- (4- methoxyphenyl) -l-hexene, processed and the crude product on silica gel with hexane / 0-5% ethyl acetate chromatography.
  • IR (KBr): 3420 (broad), 2940, 1705, 1695, 1607, 1572, 1515, 1458, 1335, 1248, 1220, 1380, 1110, 1038, 1012, 970, 846, cm ' 1
  • the crude product is dissolved in 0.6 ml of methanoi, 0.3 ml of 2N sodium hydroxide solution is added and the mixture is stirred for 48 hours at room temperature.
  • the reaction mixture is concentrated, acidified to pH 3 with 2N sulfuric acid, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. 15 mg of the title compound are obtained as a colorless oil.
  • Example 1 D Under the conditions of Example 1 D, 510 mg of methyl 3- (6-formyl-3-hydroxy-2-pyridyl) propionate with 730 mg (IE) -6-bromo-1- (4-methoxyphenyl) -1- converted hexene, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate. 284 mg of methyl 3- ⁇ 6-formyl-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl ⁇ propionate of melting point 66-69 ° C are obtained.
  • Example 1 B Under the conditions of Example 1 B, a solution of 22 g of 2-iodo-3-methoxypyridine-6-carboxylic acid methyl ester in 50 ml of dimethylformamide in the presence of 5.3 g of bis-triphenylphosphine palladium-II-chloride, 25.9 g of potassium carbonate and 23.4 g of tetrabutylammonium bromide reacted with 12.6 g of methyl acrylate, processed and the crude product on silica gel with hexane / 0-30% ethyl acetate chromatography. 11 g of 3- (3-methoxy-6-methoxycarbonyl-2-pyridyl) - (2E) -2-propenoic acid methyl ester of melting point 123-126 ° C. are obtained.
  • Example 2 Under the conditions of Example 1 C, a solution of 11 g of 3- (3-methoxy-6-methoxycarbonyl-2-pyridyl) - (2E) -2-propenoic acid methyl ester in 600 ml of methanol in the presence of 2.2 g of 10 % palladium catalyst on activated carbon, hydrogenated, processed and the crude product on silica gel with hexane / 0-25%
  • Example 1 D Under the conditions of Example 1 D, 440 mg of tert-butyl 3- (6-tert-butoxycarbonyl-3-hydroxy-2-pyridyl) -propionate with 367 mg (IU) -6-bromo-l- (4-methoxyphenyl) -l-hexene reacted, processed and the crude product chromatographed on silica gel with hexane / 0-8% ethyl acetate. 350 mg of tert-butyl 3- ⁇ 6-tert-butoxycarbonyl-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl ⁇ - are obtained as an oil.
  • a solution of 100 g of 4-bromophenylacetic acid in 1.5 l of methanol is mixed with 232 g of Amberlyst 15 and the suspension is stirred for 48 hours at room temperature.
  • the reaction mixture is suctioned off over kieselguhr, the filter residue is washed with dichloromethane and the filtrate is concentrated.
  • the backlog is in Ethyl acetate was added, washed with 10% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium suifate and concentrated.
  • 106 g of 4-bromophenylacetic acid methyl ester are obtained as an oil.
  • Example 1 D Under the conditions of Example 1 D, 600 mg of 3- ⁇ 3-hydroxy-6- [2- (4-methoxycarbonyimethylphenyl) ethynyl] -2-pyridyl ⁇ propionic acid methyl ester with 460 mg (IU) -6-bromo- l- (4-methoxyphenyl) -l-hexene reacted, processed and the crude product on gravel egg with hexane / 0-10% ethyl acetate chromatographies.
  • Example 14A Under the conditions of Example 14A, a solution of 500 mg of 3- ⁇ 3-hydroxy-6- [2- (4-methoxycarbonylmethylphenyl) -ethynyl] -2-pyridyl ⁇ -propionic acid methyl ester in 5 ml of methanol in the presence of 50 mg of 10% palladium catalyst on activated carbon hydrogenated and processed. The raw product is on
  • Example 5A Under the conditions of Example 5A, 3.15 g of N-benzenesulfonyl-4-iodobenzoic acid are reacted with 1.3 g of trimethylsilylacetylene, processed and the crude product is chromatographed on silica gel with dichloromethane 0-5% methanol. 3.1 g of N-benzenesulfonyl-4- (2-trimethylsilylethynyl) benzoic acid amide are obtained as an oil.
  • Example 5 D Under the conditions of Example 5 A, 1.31 g of the crude N-benzenesulfonyl-4-enthinylbenzoic acid amide are mixed with 1.9 g of 3- ⁇ 6-iodo-3- [6- (4-methoxyphenyl) - (5E ) -5-hexenyloxy] -2-pyridyl ⁇ -propionic acid methyl ester,:., Processed and the crude product chromatographed on silica gel with dichloromethane 0-5% methanol.
  • Methyl bromo nicotinate reacted with 2.43 g trimethylsilylacetylene, processed and the crude product chromatographed on silica gel with hexane 0-5% ethyl acetate. 734 mg of methyl 5- (2-trimethylsilylethynyl) nicotinate are obtained as an oil.
  • Tetrabutylammonium fluoride reacted in tetrahydrofuran, processed and the residue chromatographed on silica gel with hexane / 0-7% ethyl acetate. 196 mg of 5-ethynyl nicotinic acid methyl ester are obtained as an oily crude product.
  • Example 5A Under the conditions of Example 5A, 6.2 g of N- (3-iodophenyl) -l, l, l-trifluoromethanesulfonamide are reacted with 2.07 g of trimethylsilylacetylene, processed and the crude product on silica gel with hexane / 0-25% ethyl acetate chromatographed. 2.72 g of N- [3- (2-trimethylsilylethynyl) phenyl] -1, l, l-trifluoromethanesulfonamide are obtained as a yellow oil.
  • Example 5A Under the conditions of Example 5A, 370 mg of the crude N- (3-ethynylphenyl) -l, l, l-trifluoromethanesulfonamide with 735 mg of 3- ⁇ 6-iodo-3- [6- (4-methoxyphenyl) - ( 5E) -5-hexenyloxy] -2-pyridyl ⁇ propionic acid methyl ester, processed, and the crude product chromatographed on silica gel with hexane 0-20% ethyl acetate.
  • Example 5A Under the conditions of Example 5A, 2 g of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) propionate are reacted with 0.8 g of methyl 4-pentynate, processed and the crude product on silica gel with hexane / 0-30 % Ethyl acetate chromatographed.
  • Example 14 A Under the conditions of Example 14 A, a solution of 1 g of 5- [3-hydroxy-2- (2-methoxycarbonylethyl) -6-pyridyl] -4-pentynate in 10 ml of methanol in the presence of 100 mg of 10% strength Palladium catalyst on activated carbon hydrogenated and processed. Chromatograph the crude product on silica gel with hexane / 0-50% ethyl acetate. 665 mg of 5- [3-hydroxy-2- (2-methoxycarbonylethyl) -6-pyridyl] pentanoic acid methyl ester of melting point 92-95 ° C. are obtained.
  • Example 1 D Under the conditions of Example 1 D, 400 mg of 3- [3-hydroxy-6- (5-hydroxy-1-pentinyl) -2-pyridyl] propionic acid methyl ester are mixed with 410 mg of (1E) -6-bromo-1- (4-methoxyphenyl) -l-hexane reacted, processed and the crude product chromatographed on silica gel with hexane / 0-27.5% ethyl acetate. 293 mg of 3- ⁇ 6- (5-
  • Example 14A Under the conditions of Example 14A, a solution of 700 mg of methyl 3- [3-hydroxy-6- (5-hydroxy-l-pentinyl) -2-pyridyl] propionate in 25 ml of methanol in the presence of 100 mg of 10% Palladium catalyst on activated carbon hydrogenated and processed. The crude product is chromatographed on silica gel with hexane 10-30% ethyl acetate.
  • Example 3C Under the conditions of Example 3C, 400 mg of methyl 3- ⁇ 6- (5-hydroxypentyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl ⁇ -prc * nionate saponified in 20 ml of methanol with 12 ml of 2N sodium hydroxide solution and processed. 322 mg of the title compound are obtained as an oil.
  • the solvent is distilled off in vacuo and the residue is chromatographed on reversed phase silica gel (RP-18 material) with water / 10-30% methanol. The desired fractions are combined, the methanol is distilled off in vacuo and the remaining aqueous solution is freeze-dried. 471 mg of the title compound are obtained as a colorless amorphous solid.
  • Example 5A Under the conditions of Example 5A, 9.2 g of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) -propionate are reacted with 4.8 g of 3-ethynylbenzoic acid, ethyl ester, processed and the crude product on silica gel with hexane (0-20% ethyl acetate chromatographed. 4.7 g of methyl 3- ⁇ 3-hydroxy-6- [2- (3-methoxycarbonylphenyl) -ethynyl] -2-pyridyl ⁇ propionate from

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Abstract

De nouveaux dérivés de pyridine répondent à la formule générale (I), dans laquelle .^_.^_.^_ désigne une liaison simple ou double; m, n, p et r désignent chacun un chiffre compris entre 0 et 5; q désigne les chiffres 1 ou 2; U désigne une liaison simple ou le groupement -CH2-CH2, -CHOH-, -CO-, -CH=CH-, -C=C-, -CO-CO- ou -CHOH-CHOH-; V désigne une liaison simple, un reste phényle ou un reste pyridyle; W désigne un atome d'hydrogène, un atome d'halogène, un groupe alkyle ayant jusqu'à 4 atomes de carbone, un groupe trifluorométhyle, une groupe alkylsulfonylamino, un groupe trifluorométhylsulfonylamino, un groupe arylsulfonylaminocarbonyle, un groupe carboxyle libre, estérifié ou amidé, ou un groupe hydroxyle; X désigne un groupe carboxyle libre, estérifié ou amidé; Y désigne un atome d'oxygène ou un groupe méthylène et Z désigne une liaison simple lorsque q désigne le chiffre 2, sinon un groupe alkyle ou alcylène ayant au maximum 8 atomes de carbone ou un reste phényle, phénoxyle ou styryle substitué le cas échéant par des groupes alkyle ayant au maximum 4 atomes de carbone, par des groupes alcoxyle ayant au maximum 4 atomes de carbone, par des groupes 1-oxoalkyle ayant au maximum 4 atomes de carbone, par des atomes d'halogènes et/ou par des groupes trifluorométhyle. L'invention concerne également les sels de ces dérivés avec des bases physiologiquement acceptables.
PCT/DE1993/000593 1992-07-21 1993-07-01 Nouveaux derives de pyridine a effet antagoniste contre les leucotrienes b¿4? WO1994002464A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP6503890A JPH07508990A (ja) 1992-07-21 1993-07-01 ロイコトリエン−ｂ↓４拮抗作用を有する新規ピリジン誘導体
AU44153/93A AU679184B2 (en) 1992-07-21 1993-07-01 New pyridine derivatives as leukcotriene B4 antagonists
EP93914599A EP0651745A1 (fr) 1992-07-21 1993-07-01 Nouveaux derives de pyridine a effet antagoniste contre les leucotrienes b 4?
US08/374,608 US5624943A (en) 1992-07-21 1993-07-01 Pyridine compounds which are useful as leukotriene-B4 -antagonists

Applications Claiming Priority (2)

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DEP4224402.1 1992-07-21
DE4224402A DE4224402A1 (de) 1992-07-21 1992-07-21 Neue Pyridin-Derivate mit Leukotrien-B¶4¶-antagonistischer Wirkung

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WO1998013347A1 (fr) * 1996-09-26 1998-04-02 Novartis Ag Acrylamides substitues par de l'aryle ayant une activite antagoniste du recepteur leucotriene b4 (ltb-4)

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GB9313145D0 (en) * 1993-06-25 1993-08-11 Smithkline Beecham Plc Process
US8729108B2 (en) * 2008-06-17 2014-05-20 Christopher J Dannaker Waterborne topical compositions for the delivery of active ingredients such as azelaic acid

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EP0276064A1 (fr) * 1987-01-12 1988-07-27 Eli Lilly And Company Agents anti-imflammatoires
EP0405116A2 (fr) * 1989-06-27 1991-01-02 Ono Pharmaceutical Co., Ltd. Acides phénylalcan(èn)oiques
WO1991018883A1 (fr) * 1990-06-07 1991-12-12 Smithkline Beecham Corporation Derives d'acide pyridyle-benzoique a liaison amide utilises dans le traitement de maladies associees aux leucotrienes
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EP0405116A2 (fr) * 1989-06-27 1991-01-02 Ono Pharmaceutical Co., Ltd. Acides phénylalcan(èn)oiques
WO1991018883A1 (fr) * 1990-06-07 1991-12-12 Smithkline Beecham Corporation Derives d'acide pyridyle-benzoique a liaison amide utilises dans le traitement de maladies associees aux leucotrienes
WO1991018879A1 (fr) * 1990-06-07 1991-12-12 Smithkline Beecham Corporation Derives d'acide phtalamique utilises dans le traitement de maladies associees aux leucotrienes
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998013347A1 (fr) * 1996-09-26 1998-04-02 Novartis Ag Acrylamides substitues par de l'aryle ayant une activite antagoniste du recepteur leucotriene b4 (ltb-4)
US6291530B1 (en) 1996-09-26 2001-09-18 Novartis Ag Aryl-substituted acrylamides with Leukotriene B4 (LTB-4) receptor antagonist activity

Also Published As

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EP0651745A1 (fr) 1995-05-10
HU9500160D0 (en) 1995-03-28
AU4415393A (en) 1994-02-14
JPH07508990A (ja) 1995-10-05
HUT71887A (en) 1996-02-28
US5624943A (en) 1997-04-29
DE4224402A1 (de) 1994-01-27
AU679184B2 (en) 1997-06-26
CA2139586A1 (fr) 1994-02-03

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